Pretomanid (pretomanid 200 mg) Dailymed

Important Administration Instructions: (2.1)

• •Pretomanid Tablets must be administered only in combination with bedaquiline and linezolid as part of the recommended dosage regimen.
• •Administer the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid by directly observed therapy (DOT).
• •Pretomanid Tablets must be administered in combination with bedaquiline and linezolid with food.
• •Doses of the combination regimen missed for safety reasons can be made up at the end of treatment; doses of linezolid alone missed due to linezolid adverse reactions should not be made up.
• •Administer Pretomanid Tablets in combination with bedaquiline and linezolid as follows: (2.2)
• • Pretomanid Tablets:
  • •Pretomanid Tablet 200 mg orally once daily for 26 weeks. Administer Pretomanid Tablets whole with water.
  • •For patients with swallowing difficulties see the full prescribing information for crushing or soaking followed by crushing instructions of the Pretomanid Tablets.
• • Bedaquiline:
  • •Bedaquiline 400 mg orally once daily for 2 weeks followed by 200 mg 3 times per week, with at least 48 hours between doses, for 24 weeks for a total of 26 weeks.
  • •Bedaquiline 200 mg orally once daily for 8 weeks followed by 100 mg once daily for 18 weeks, for a total of 26 weeks.
• • Linezolid:
  • •Linezolid Preferred: 600 mg orally once daily for 26 weeks. Alternative: 1,200 mg orally once daily for 26 weeks.
  • •If myelosuppression, peripheral neuropathy, or optic neuropathy occurs, reduce or interrupt linezolid dosing as necessary.

2.1 Important Administration Instructions

• • Pretomanid Tablets must be administered only in combination with bedaquiline and linezolid as part of the recommended dosage regimen [see Dosage and Administration (2.2)].
• • Administer the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid by directly observed therapy (DOT).
• • Pretomanid Tablets must be administered in combination with bedaquiline and linezolid with food [see Clinical Pharmacology (12.3)].
• • Emphasize the need for compliance with the full course of therapy to patients [see Patient Counseling Information (17)].
• • If the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid is interrupted by a healthcare provider for safety reasons, missed doses can be made up at the end of the treatment; doses of linezolid alone missed due to linezolid adverse reactions should not be made up [see Dosage and Administration (2.4)].
• • Dosing of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can be extended beyond 26 weeks, if necessary [see Clinical Studies (14)].

2.2 Recommended Dosage

Pretomanid Tablets must be administered in combination with bedaquiline and linezolid with food [see Clinical Pharmacology (12.3) ]. The recommended dosage and duration for Pretomanid Tablets, bedaquiline and linezolid when administered in the combination regimen are as follows:

Pretomanid Tablets:

• • Administer Pretomanid Tablet 200 mg orally (1 tablet of 200 mg), once daily, for 26 weeks with food.
• • Administer Pretomanid Tablets whole with water.
• • For adult patients with swallowing difficulties, use one of the following two methods:
• A) Crush and Suspend Pretomanid Tablets
• • Crush and suspend Pretomanid Tablet in one teaspoon (approximately 5 mL) of room temperature water in a drinking cup and mix well by vigorous stirring.
• • Orally administer the contents of the cup immediately.
• • To ensure no tablet residual is left in the cup, rinse with an additional one teaspoon (approximately 5 mL) of water and orally administer the contents of the cup immediately.
• • Do not store the mixture for later use.
• B) Soak and then Crush Pretomanid Tablets
• • Soak Pretomanid Tablet for 4 to 5 minutes in one teaspoon (approximately 5 mL) of room temperature water in a drinking cup and then any remaining solid should be crushed. Mix the contents of the cup well by vigorous stirring.
• • Orally administer the contents of the cup immediately.
• • To ensure no tablet residual is left in the cup, rinse with an additional one teaspoon (approximately 5 mL) of water and orally administer the contents of the cup immediately.
• • Do not store the mixture for later use.

Bedaquiline:

Use one of the following two dosage regimens of bedaquiline:

• • Bedaquiline 400 mg orally once daily for 2 weeks followed by 200 mg 3 times per week, with at least 48 hours between doses, for 24 weeks, for a total of 26 weeks.
• • Bedaquiline 200 mg orally once daily for 8 weeks followed by 100 mg once daily for 18 weeks, for a total of 26 weeks.

Linezolid:

• • Preferred linezolid dosage regimen: 600 mg orally once daily for 26 weeks. If myelosuppression, peripheral neuropathy, or optic neuropathy occurs, reduce linezolid dosage to 300 mg once daily or interrupt linezolid dosing [see Dosage and Administration (2.4), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.1)].
• • Alternative linezolid dosage regimen: 1,200 mg orally once daily for 26 weeks. If myelosuppression, peripheral neuropathy, or optic neuropathy occurs, reduce linezolid dosage to 600 mg once daily, further reduce linezolid dosage to 300 mg once daily, or interrupt linezolid dosing [see Dosage and Administration (2.4), Warnings and Precautions (5.3, 5.4), and Adverse Reactions (6.1)].

2.3 Assessments Prior to Initiating the Combination Regimen of Pretomanid Tablets, Bedaquiline, and Linezolid

• •Assess for symptoms and signs of liver disease (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly). Obtain laboratory tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin) [see Warnings and Precautions (5.2) ].
• •Obtain complete blood count [see Warnings and Precautions (5.3) ]. Obtain serum potassium, calcium, and magnesium and correct if abnormal [see Warnings and Precautions (5.5) ]. Obtain an ECG before initiation of treatment [see Warnings and Precautions (5.5) ].

2.4 Discontinuation of Dosing

If either bedaquiline or Pretomanid Tablets are discontinued, the entire combination regimen should also be discontinued.

If linezolid is permanently discontinued during the initial four consecutive weeks of treatment, bedaquiline and Pretomanid Tablets should also be discontinued. If linezolid is discontinued after the initial four weeks of consecutive treatment, continue administering bedaquiline and Pretomanid Tablets [see Dosage and Administration (2.2)].

• •Hepatic adverse reactions were reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Monitor symptoms and signs and liver‑related laboratory tests. Interrupt treatment with the entire regimen if evidence of liver injury occurs. (5.2)
• •Myelosuppression was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Monitor complete blood counts. Decrease or interrupt linezolid dosing if significant myelosuppression develops or worsens. (5.3)
• •Peripheral and optic neuropathy were reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Monitor visual function. Obtain an ophthalmologic evaluation if there are symptoms of visual impairment. Decrease or interrupt linezolid dosing if neuropathy develops or worsens. (5.4)
• •QT prolongation was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Use with drugs that prolong the QT interval may cause additive QT prolongation. Monitor ECGs. Discontinue the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops. (5.5)
• •Reproductive effects: Pretomanid caused testicular atrophy and impaired fertility in male rats. Advise patients of reproductive toxicities seen in animal studies and that the potential effects on human male fertility have not been adequately evaluated. (5.7, 13.1)
• •Lactic acidosis was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Consider interrupting linezolid or the entire combination regimen of Pretomanid Tablets, bedaquiline, and linezolid dosing if significant lactic acidosis develops. (5.8)

5.1 Risks Associated with the Combination Treatment Regimen

Pretomanid Tablet is indicated for use as part of a regimen in combination with bedaquiline and linezolid. Refer to the prescribing information for bedaquiline and linezolid for additional risk information. Warnings and Precautions related to bedaquiline and linezolid also apply to their use in the combination regimen with Pretomanid Tablets.

5.2 Hepatotoxicity

Hepatic adverse reactions were reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Warnings and Precautions (5.1) , and Adverse Reactions (6.1) ]. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid [see Indications and Usage (1) ] while on Pretomanid Tablets, especially in patients with impaired hepatic function.

Monitor symptoms and signs (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at a minimum at baseline, at two weeks, and then monthly while on treatment and as needed. If evidence of new or worsening liver dysfunction occurs, test for viral hepatitides and discontinue other hepatotoxic medications. Interrupt treatment with the entire regimen if:

• •Aminotransferase elevations are accompanied by total bilirubin elevation greater than 2 times the upper limit of normal.
• •Aminotransferase elevations are greater than 8 times the upper limit of normal.
• •Aminotransferase elevations are greater than 5 times the upper limit of normal and persist beyond 2 weeks.

5.3 Myelosuppression

Myelosuppression (including anemia, leukopenia, thrombocytopenia, and pancytopenia) was reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Myelosuppression is a known adverse reaction of linezolid. Anemia can be life threatening [see Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. When linezolid dosing, as part of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, was reduced, interrupted, or discontinued, the observed hematologic abnormalities were reversible. Complete blood counts should be monitored at a minimum at baseline, at two weeks, and then monthly in patients receiving linezolid as part of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Decreasing linezolid to half the initial dose or interrupting linezolid dosing should be considered in patients who develop or have worsening myelosuppression [see Dosage and Administration (2.2)].

5.4 Peripheral and Optic Neuropathy

Peripheral neuropathy and optic neuropathy were reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Warnings and Precautions (5.1), and Adverse Reactions (6.1)]. Neuropathy is a known adverse reaction of long-term linezolid use. Neuropathy associated with linezolid is generally reversible or improved with appropriate monitoring and interruption, dose reduction, or discontinuation of linezolid dosing. When improvement in the peripheral neuropathy is observed, consider resuming linezolid at half the initial dose [see Dosage and Administration (2.2)]. Monitor visual function in all patients receiving the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid; if a patient experiences symptoms of visual impairment, interrupt linezolid dosing and obtain prompt ophthalmologic evaluation.

5.5 QT Prolongation

QT prolongation was reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) , and Clinical Pharmacology (12.2) ]. QT prolongation is a known adverse reaction of bedaquiline. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor these electrolytes if QT prolongation is detected [see Adverse Reactions (6.1) ].

The following may increase the risk for QT prolongation when patients are receiving bedaquiline as part of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid: a history of Torsade de Pointes, congenital long QT syndrome, ongoing hypothyroidism, ongoing bradyarrhythmia, uncompensated heart failure, or serum calcium, magnesium, or potassium levels below the lower limits of normal. If necessary, bedaquiline treatment initiation could be considered in these patients after a favorable benefit-risk assessment and with frequent ECG monitoring.

Discontinue the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms (confirmed by repeat ECG). If syncope occurs, obtain an ECG to detect QT prolongation.

5.6 Drug Interactions

Pretomanid may be in part metabolized by CYP3A4 [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Avoid co‑administration of strong or moderate CYP3A4 inducers, such as rifampin or efavirenz, during treatment with pretomanid.

5.7 Reproductive Effects

Pretomanid caused testicular atrophy and impaired fertility in male rats. Advise patients of reproductive toxicities seen in animal studies and that the potential effects on human male fertility have not been adequately evaluated [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1) ].

5.8 Lactic Acidosis

Lactic acidosis was reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ]. Lactic acidosis is a known adverse reaction of linezolid. Patients who develop recurrent nausea or vomiting should receive immediate medical evaluation, including evaluation of bicarbonate and lactic acid levels, and interruption of linezolid or the entire combination regimen of Pretomanid Tablets, bedaquiline, and linezolid should be considered.

6 Adverse Reactions

The following serious adverse reactions are discussed here and elsewhere in the labeling:

• •Hepatotoxicity [see Warnings and Precautions (5.2)]
• •Myelosuppression [see Warnings and Precautions (5.3)]
• •Peripheral and Optic Neuropathy [see Warnings and Precautions (5.4)]
• •QT Prolongation [see Warnings and Precautions (5.5)]
• •Reproductive Effects [see Warnings and Precautions (5.7)]
• •Lactic Acidosis [see Warnings and Precautions (5.8)]

Most common adverse reactions (≥ 10%) are peripheral neuropathy, anemia, nausea, acne, vomiting, increased transaminases, headache, musculoskeletal pain, dyspepsia, rash, pruritus, decreased appetite, abdominal pain, pleuritic pain, increased gamma-glutamyltransferase, hemoptysis and hyperamylasemia. (6)

 

To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

When Pretomanid Tablets are administered in combination with bedaquiline and linezolid, refer to the prescribing information for the respective drugs for a description of the adverse reactions associated with their use.

Approximately 3100 subjects have been exposed to Pretomanid Tablets, either alone or as part of a combination therapy in clinical trials.

The registrational trial, Trial 1 (NCT02333799), was a single-arm, open-label trial conducted in three sites in South Africa in which adult patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug or pulmonary TB resistant to isoniazid and rifampin, who were treatment-intolerant or non-responsive to standard therapy received the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 6 months (extendable to 9 months) with 24 months of follow-up. One hundred and nine patients were treated; 76% were black, and 23% were of mixed race. Their ages ranged from 17 years to 60 years (mean 36 years), and all patients were from South Africa. Fifty-six (51%) patients were HIV-positive. There were 8 deaths. Six patients died while receiving treatment; all surviving patients, excluding one patient who withdrew consent, completed treatment. Two patients died during follow-up at Day 369 and Day 486, respectively.

Trial 2 (NCT03086486) was a phase 3 partially-blinded, randomized trial assessing the safety and efficacy of various doses and treatment durations of linezolid in combination with Pretomanid Tablets plus bedaquiline in patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug, or pulmonary TB resistant to rifamycins and either a fluoroquinolone or a second line injectable antibacterial drug, or pulmonary TB resistant to isoniazid and rifampin who were treatment intolerant or non-responsive to standard therapy.

A total of 181 patients were randomized to one of the 4 treatment arms, Pretomanid Tablets plus bedaquiline plus either 1,200 mg or 600 mg of linezolid for 26 weeks or for 9 weeks (not an approved dosing regimen), followed by a linezolid placebo for 17 weeks. Males represented 67% of the patients in the trial and the median age of all patients was 36 years. 64% of patients were White and the remaining patients were Black (36%). The treatment groups were comparable with respect to demographic characteristics. Most patients (93%) completed treatment. One patient died in the linezolid 1,200 mg for 9 weeks (not an approved dosing regimen) arm.

Table 1 summarizes the incidence of select adverse reactions occurring in ≥ 5% of patients treated for 26 weeks in Trials 1 and 2.

Table 1: Select Adverse Reactions (All Grades) Reported in ≥ 5% of Patients Receiving the Combination Regimen of Pretomanid Tablets, Bedaquiline, and Linezolid in Trials 1 and 2

	Pretomanid Tablets, Bedaquiline and Linezolid (1,200 mg)Combination Regimen(N = 154)	Pretomanid Tablets, Bedaquiline and Linezolid (600 mg)Combination Regimen(N = 45)
Adverse Reactions	All Gradesn (%)	All Gradesn (%)
Peripheral neuropathySelect terms are collapsed, as follows: peripheral neuropathy (burning sensation, hypoesthesia, hyporeflexia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy, sensory disturbance); anemia (anemia); acne (acne, dermatitis acneiform); transaminases increased (alanine aminotransferase [ALT]) increased, aspartate aminotransferase [AST] increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, liver function test increased, transaminases increased); musculoskeletal pain (arthralgia, back pain, costochondritis, myalgia, pain in extremity); rash (rash, rash erythematous, rash maculo-papular, rash papular, rash vesicular); pruritus (pruritus, pruritus generalized, rash pruritic); abdominal pain (abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness); hyperamylasemia (amylase increased, hyperamylasemia); hypertension (blood pressure increased, hypertension); cough (cough, productive cough); visual impairment (vision blurred, visual acuity reduced, visual impairment); neutropenia (neutropenia); hyperlipasemia (hyperlipasemia, lipase increased).	105 (68)	10 (22)
Anemia	48 (31)
Nausea	46 (30)
Acne	44 (29)	6 (13)
Vomiting	40 (26)
Transaminases increased	39 (25)	11 (24)
Headache	34 (22)
Musculoskeletal pain	34 (22)
Dyspepsia	30 (19)
Rash	29 (19)
Pruritus	25 (16)	3 (7)
Decreased appetite	24 (16)
Abdominal pain	22 (14)
Pleuritic pain	22 (14)	4 (9)
Gamma-glutamyltransferase increased	20 (13)
Hemoptysis	17 (11)
Hyperamylasemia	15 (10)
Diarrhea	14 (9)
Hypertension	14 (9)
Cough	13 (8)
Visual impairment	13 (8)
Hypoglycemia	12 (8)
Neutropenia	12 (8)	3 (7)
Abnormal loss of weight	11 (7)
Constipation	9 (6)
Gastritis	9 (6)
Hyperlipasemia	9 (6)
Insomnia	9 (6)
Dry skin	8 (5)

 

The following select adverse reactions were reported in patients receiving the combination regimen of Pretomanid Tablets, bedaquiline and linezolid (1,200 mg) at a rate of less than 5% in Trials 1 and 2:

Gastrointestinal Disorders: pancreatitis, dysgeusia

Investigations: blood creatine phosphokinase increase, blood creatinine increase, blood alkaline phosphatase increase

Blood and Lymphatic System Disorders: leukopenia, thrombocytopenia

Metabolism and Nutrition Disorders: hypomagnesemia, hyperglycemia, hypokalemia, hyperkalemia, hyponatremia

Nervous System Disorders: dizziness, seizure

The following select adverse reactions were reported in patients receiving the combination regimen of Pretomanid Tablets, bedaquiline and linezolid (600 mg) at a rate of less than 5% in Trial 2:

Blood and Lymphatic System Disorders: anemia, thrombocytopenia

Metabolism and Nutrition Disorders: decreased appetite, hyperlipasemia, hypoglycemia, hypophosphatemia, hypomagnesemia, hyperkalemia

Psychiatric Disorders: insomnia

Nervous System Disorders: headache

Vascular Disorders: hypertension

Respiratory, Thoracic and Mediastinal Disorders: cough, hemoptysis

Gastrointestinal Disorders: abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting

Skin and Subcutaneous Tissue Disorders: dry skin, rash

Musculoskeletal and Connective Tissue Disorders: musculoskeletal pain

Table 2 summarizes select laboratory abnormalities in patients treated for 26 weeks in Trials 1 and 2.

Table 2: Select Laboratory Abnormalities in Clinical Trials

ULN = upper limit of normal
Parameter Multiples of Upper Limit of Normal (x ULN)	Combination Regimen of Pretomanid Tablets, Bedaquiline, and Linezolid (1,200 mg)(N = 154)n (%)	Combination Regimen of Pretomanid Tablets, Bedaquiline, and Linezolid (600 mg)(N = 45)n (%)
Transaminases and Bilirubin
Alanine Aminotransferase (ALT)
> 3 and ≤ 5 X ULN	13 (8)	3 (7)
> 5 and ≤ 8 X ULN	6 (4)	0 (0)
> 8 X ULN	1 (1)	1 (2)
Aspartate Aminotransferase (AST)
> 3 and ≤ 5 X ULN	7 (5)	0 (0)
> 5 and ≤ 8 X ULN	3 (2)	0 (0)
> 8 X ULN	1 (1)	1 (2)
Total Bilirubin
> 1 X ULN and ≤ 2 X ULN	8 (5)	1 (2)
> 2 X ULN	2 (1)	1 (2)
Hematology
Hemoglobin
≤ 7.9 g/dL	6 (4)	0 (0)
Neutrophils Absolute Count
≤ 749/mm3	6 (4)	1 (2)
Platelets
≤ 49,999/mm3	2 (1)	0 (0)
Serum Chemistry
Lipase
> 2 X ULN	7 (5)	2 (4)

 

In Trial 1, 28% of patients experienced increased transaminases. Except for one patient who died due to pneumonia and sepsis, all patients who experienced increased transaminases were able to continue therapy and complete the full course of treatment. In Trial 2, 47 of 181 patients (26%) had one or more liver-related adverse reactions, with similar numbers in each group.

Myelosuppression is a known adverse reaction of linezolid. In Trial 1, the most common hematopoietic cytopenia was anemia (37%). The majority of cytopenias began after 2 weeks of treatment. Three patients experienced cytopenias that were considered serious: neutropenia in 1 patient and anemia in 2 patients. All 3 serious adverse reactions resulted in interruption of linezolid or all components of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, and all resolved.

In Trial 2, there was a greater incidence of myelosuppression, 29% versus 13%, for the 1,200 mg compared to the 600 mg linezolid 26-week group. Most of the myelosuppression-related adverse reactions were either grade 1 or grade 2 in severity.

In the combined study data for Trial 1 and Trial 2, 2 patients reported serious adverse reactions of anemia with linezolid 1,200 mg, and none were reported in the 600 mg group.

Peripheral neuropathy is a known adverse reaction of linezolid. In Trial 1, peripheral neuropathy was reported in 81% of patients. Most of these adverse reactions (64%) occurred after 8 weeks of treatment and resulted in dosing interruption, dose reduction, or discontinuation of linezolid. Severe, moderate, and mild peripheral neuropathy occurred in 22%, 32%, and 26% of patients, respectively. No adverse reaction related to peripheral neuropathy led to a discontinuation of the entire study regimen.

In Trial 2, 17 (38%) patients reported an adverse reaction of peripheral neuropathy in the 1,200 mg 26-week treatment group; one of these reactions led to treatment discontinuation. In the 600 mg 26-week treatment group, 10 (22%) patients reported peripheral neuropathy, and none required linezolid treatment interruption or treatment discontinuation.

Optic neuropathy is a known adverse reaction of linezolid. Two patients (2%) in Trial 1 developed optic neuropathy after 16 weeks of treatment. Both were serious, confirmed on retinal examination as optic neuropathy/neuritis, and resulted in discontinuation of linezolid; both adverse reactions resolved.

Overall, patients administered a linezolid dose of 600 mg twice daily had a similar safety profile to those administered a dose of 1,200 mg once daily.

In Trial 2 overall, 4 (2%) patients reported an adverse reaction of optic neuropathy. All 4 patients were in the 1,200 mg linezolid 26-week treatment group (9%). The maximum severity was grade 1 (mild) for 1 patient, grade 2 (moderate) for 2 patients, and grade 3 (severe) for 1 patient. All patients had linezolid permanently discontinued except 1 patient who had already completed treatment when the adverse reaction occurred. Onset of optic neuropathy occurred after 3 months of treatment, and resolved.